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Phytotherapy for benign prostatic hyperplasia - Graminex

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P R O S T A T E S U P P O R T :<br />

GRAMINEX Flower Pollen Extract<br />

<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />

Timothy J Wilt*, Areef Ishani, Indulis Rutks and Roderick MacDonald<br />

Minneapolis VA Center <strong>for</strong> Chronic Diseases Outcomes Research, 1 Veterans Drive (111-0),<br />

Minneapolis, MN 55417, USA<br />

Abstract<br />

Objective<br />

To systematically review the existing evidence regarding the efficacy and safety of phytotherapeutic<br />

compounds used to treat men with symptomatic <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong> (BPH).<br />

Design<br />

Randomized trials were identified searching MEDLINE (1966±1997), EMBASE Phytodok, the Cochrane<br />

Library, bibliographies of identified trials and review articles, and contact with relevant authors and drug<br />

companies. The studies were included if men had symptomatic <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong>, the<br />

intervention was a phytotherapeutic reparational one or combined, a control group received placebo or<br />

other pharmacologic therapies <strong>for</strong> BPH, and the treatment duration was at least 30 days. Key data were<br />

extracted independently by two investigators.<br />

Results<br />

A total of 44 studies of six phytotherapeutic agents (Serenoa repens, Hypoxis rooperi, Secale cereale,<br />

Pygeum africanum, Urtica dioica, Curcubita pepo) met inclusion criteria and were reviewed. Many studies<br />

did not report results in a method allowing meta-analysis. Serenoa repens, extracted from the saw<br />

palmetto, is the most widely used phytotherapeutic agent <strong>for</strong> BPH. A total of 18 trials involving 2939 men<br />

were reviewed. Compared with men receiving placebo, men taking Serenoa repens reported greater<br />

improvement of urinary tract symptoms and flow measures. Serenoa repens decreased nocturia<br />

(weighted mean difference .WMD. 20:76 times per evening; 95% CI . 21:22 to 20.32; n . 10 studies) and<br />

improved peak urine flow.WMD . 1:93 ml s21; 95% CI . 0:72 to 3.14, n . 8 studies). Men treated with<br />

Serenoa repens rated greater improvement of their urinary tract symptoms versus men taking placebo<br />

(risk ratio of improvement. 1:72; 95% CI . 1:21 to 2.44, n . 8 studies). Improvement in symptoms of BPH<br />

was comparable to men receiving the finasteride. Hypoxis rooperi (n . 4 studies, 519 men) was also<br />

demonstrated to be effective in improving symptom scores and flow measures compared with placebo.<br />

For the two studies reporting the International Prostate Symptom Score, the WMD was 24.9 IPSS points<br />

(95% CI . 26:3 to 23.5, n . 2 studies) and the WMD <strong>for</strong> peak urine flow was 3.91 ml s21 (95% CI . 0:91 to<br />

6.90, n . 4 studies). Secale cereale (n . 4 studies, 444 men) was found to modestly improve overall<br />

urological symptoms. Pygeum africanum (n . 17 studies, 900 men) may be a useful treatment option <strong>for</strong><br />

BPH. However, review of the literature has found inadequate reporting of outcomes which currently limit<br />

the ability to estimate its safety and efficacy. The studies involving Urtica dioica and Curcubita pepo are<br />

limited although these agents may be effective combined with other plant extracts such as Serenoa and<br />

Pygeum. Adverse events due to phytotherapies were reported to be generally mild and infrequent.<br />

Conclusions<br />

Randomized studies of Serenoa repens, alone or in combination with other plant extracts, have provided<br />

the strongest evidence <strong>for</strong> efficacy and tolerability in treatment of BPH in comparison with other<br />

phytotherapies. Serenoa repens appears to be a useful option <strong>for</strong> improving lower urinary tract symptoms<br />

<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />

1 | P a g e


and flow measures. Hypoxis rooperi and Secale cereal also appear to improve BPH symptoms although<br />

the evidence is less strong <strong>for</strong> these products. Pygeum africanum has been studied extensively but<br />

inadequate reporting of outcomes limits the ability to conclusively recommend it. There is no convincing<br />

evidence supporting the use of Urtica dioica or Curcubita pepo alone <strong>for</strong> treatment of BPH. Overall,<br />

phytotherapies are less costly, well tolerated and adverse events are generally mild and infrequent.<br />

Future randomized controlled trials using standardized preparations of phytotherapeutic agents with<br />

longer study durations are needed to determine their long-term effectiveness in the treatment of BPH.<br />

Keywords: <strong>Phytotherapy</strong>, Benign <strong>prostatic</strong> <strong>hyperplasia</strong>, Randomized controlled trials, Systematic reviews, Meta-analysis, Public<br />

health nutrition: 3(4a), 459±472 459<br />

<strong>Phytotherapy</strong> or the use of plant extracts <strong>for</strong><br />

treatment of lower urinary tract symptoms<br />

(LUTS) consistent with <strong>benign</strong> <strong>prostatic</strong><br />

<strong>hyperplasia</strong> (BPH) was first described in Egypt<br />

in the 15th century BC1. <strong>Phytotherapy</strong> is<br />

common in Europe and is increasing in the<br />

Western Hemisphere. In 1998, the sale of<br />

botanical medications in the United States was<br />

$1.5 billion per year and the use of<br />

phytotherapeutic compounds increased nearly<br />

70% among US adults 2,3. About 30<br />

phytotherapeutic compounds are used <strong>for</strong> the<br />

treatment of BPH (Table 1). Phytotherapeutic<br />

agents represent nearly half the medications<br />

dispensed <strong>for</strong> treatment of BPH in Italy,<br />

compared with 5% <strong>for</strong> alpha-blockers and 5% <strong>for</strong><br />

5a-reductase inhibitors 4. In Germany and<br />

Austria, phytotherapy is the first-line treatment<br />

<strong>for</strong> mild to moderate lower urinary tract<br />

symptoms and represents more than 90% of<br />

drugs prescribed <strong>for</strong> treatment of BPH. In the<br />

United States, phytotherapies <strong>for</strong> BPH are<br />

available as nonprescription dietary<br />

supplements. Nearly a quarter of men attending<br />

a United States urology clinic who had<br />

previously treated BPH indicated they had used<br />

phytotherapeutic agents <strong>for</strong> self-treatment of<br />

urinary tract symptoms 5.<br />

Phytotherapies are often promoted to ‘maintain<br />

a healthy prostate’ and as natural and harmless<br />

treatment of BPH symptoms. Despite their<br />

popularity with the public there has been<br />

reluctance among many practitioners to routinely<br />

recommend these products. This is because of<br />

uncertainty regarding their efficacy and safety<br />

6,7. Most phytotherapeutic compounds are<br />

unlicensed and do not require evidence of<br />

efficacy, safety or purity. There have been over<br />

40 published randomized controlled trials<br />

evaluating the efficacy of phytotherapy <strong>for</strong><br />

symptomatic BPH in approximately 5000 men.<br />

Many more trials are in progress and should<br />

provide needed evidence regarding the role of<br />

phytotherapeutic products.<br />

Systematic reviews of the existing literature<br />

provide a systematic assembly of the results of<br />

primary investigations using strategies that limit<br />

bias and random error 8. Systematic reviews<br />

efficiently integrate unmanageable amounts of<br />

in<strong>for</strong>mation and provide results that allow <strong>for</strong><br />

rational decision making. They can establish<br />

whether findings are consistent and generalized<br />

or whether findings vary by subsets. If clinically<br />

and statistically appropriate, a quantitative<br />

summary (meta-analysis) can be per<strong>for</strong>med<br />

resulting in statistical pooling of results and<br />

enhancement of the estimates of therapeutic<br />

effects and risk estimates. This is especially<br />

helpful when a large number of small trials have<br />

been conducted or when results from<br />

comparable studies provide differing results.<br />

Systematic reviews also identify gaps in existing<br />

evidence and make recommendations <strong>for</strong> future<br />

research to close these scientific and clinical<br />

gaps. Phytotherapeutic compounds Serenoa<br />

repens (saw palmetto) background the most<br />

widely used phytotherapeutic agent <strong>for</strong> BPH is<br />

the extract of the dried ripe fruit from the<br />

American dwarf palm plant, saw palmetto,<br />

Serenoa repens (also known by its botanical<br />

name as Sabal serrulata). Serenoa repens has<br />

been approved in France and Germany <strong>for</strong><br />

treatment of BPH. Berries from saw palmetto<br />

were first used by the American Indians in the<br />

southeast United States in the early 1700s to<br />

treat testicular atrophy, erectile dysfunction, and<br />

prostate gland swelling or inflammation 1. The<br />

medicinal value of Serenoa repens <strong>for</strong> relief of<br />

prostate gland swelling has been reported since<br />

the 1800s. The mechanism of action of Serenoa<br />

repens has been investigated in several in vitro<br />

or indirect in vivo studies and has not been<br />

definitively defined. The mechanism may include<br />

alteration of cholesterol metabolism,<br />

antioestrogenic, anti-androgenic (including 5areductase<br />

inhibitor activity), anti-inflammatory<br />

<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />

2 | P a g e


effects, and a decrease in available sex<br />

hormone binding globulin 9±12.<br />

Results of studies a systematic review and<br />

meta-analysis of randomized trials assessed the<br />

existing evidence regarding efficacy and safety<br />

of Serenoa repens in men with symptomatic<br />

BPH 13. Studies were identified through a<br />

search of MEDLINE (1966±1997), EMBASE,<br />

Phytodok, the Cochrane Library, bibliographies<br />

of identified trials and review articles, and<br />

contact with relevant authors and drug<br />

companies. Randomized trials were included if<br />

participants had symptomatic BPH, the<br />

intervention was a preparation of Serenoa<br />

repens alone or in combination with other<br />

phytotherapeutic agents, a control group<br />

received placebo or other pharmacologic<br />

therapies <strong>for</strong> BPH, and the treatment duration<br />

was at least 30 days. Two investigators<br />

independently extracted key data on design<br />

features, subject characteristics, therapy<br />

allocation and outcomes of the studies. A total of<br />

18 studies involving almost 3000 men were<br />

identified and analysed 14±31 (Tables 2±5).<br />

Many studies did not report results in a method<br />

that permitted quantitative meta-analysis.<br />

Sixteen trials were double blinded, 14 were<br />

placebo controlled and four involved Serenoa<br />

repens in combination with other<br />

phytotherapeutic agents. The average study<br />

duration was 9 weeks (range 4±48 weeks) and<br />

the average age of enrollees was 65 years.<br />

Baseline characteristics regarding prostate<br />

volume, urine flow rates and symptom scale<br />

scores were comparable with previous trials<br />

evaluating pharmacologic management of BPH.<br />

The available data indicate that Serenoa repens<br />

(alone or in combination with other<br />

phytotherapeutic agents) improves urinary<br />

symptoms and flow measures (Figs 1±3).<br />

Compared with placebo, saw palmetto improved<br />

urinary symptom scores by 28% and nocturia by<br />

25% (the weighted mean difference .WMD.20:76<br />

times per evening; 95% CI . 21:22 to 20.32; n .<br />

10 studies). Peak urine flow was improved by<br />

24% (WMD . 1:93 ml s21; 95% CI . 0:72 to 3.14,<br />

n . 8 studies), mean urine flow by 28% (2.22 ml<br />

s21; data not shown), and residual urine volume<br />

by 43% (222.05 ml; data not shown). Men taking<br />

Serenoa repens were more likely to report<br />

improvement in urinary symptoms than men<br />

taking placebo (73.6% vs. 50.9%; risk ratio .<br />

1:76). Adverse effects were generally mild and<br />

comparable with placebo. Compared with<br />

finasteride17,30, saw palmetto provided similar<br />

<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />

responses in urologic symptom scores (0.37<br />

International Prostate Symptom Score (IPSS)<br />

points), nocturia (20.20 times per evening) and<br />

flow measures. Saw palmetto was associated<br />

with a lower rate of erectile dysfunction than<br />

finasteride (1.1% vs. 4.9%; P , 0:001) and<br />

reduced neither prostate size nor prostate<br />

specific antigen (PSA) levels. Critics have stated<br />

that comparing saw palmetto with finasteride<br />

might be showing equivalency to placebo.<br />

However, previous trials and meta-analyses<br />

have demonstrated that finasteride provides<br />

symptomatic improvement in men with prostate<br />

glands .40 g, a size comparable to those<br />

enrolled in this study 32,33.<br />

The treatment effect sizes noted with saw<br />

palmetto were comparable to effects reported<br />

with other pharmacologic agents, such as<br />

finasteride. However, the results should be<br />

viewed cautiously. Studies utilized different<br />

doses and preparations of Serenoa repens<br />

(including combination preparations). The most<br />

extensively investigated preparation of Serenoa<br />

repens is manufactured in France and sold as<br />

Permixon. The most commonly reported dosage<br />

was 160 mg twice per day. Many studies did not<br />

report outcome data in a consistent fashion.<br />

Only three studies reported validated urologic<br />

symptom scales. Trials were of short duration<br />

with only two studies having follow-up of at least<br />

phytotherapy <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />

463 6 months’ duration. There<strong>for</strong>e, it is not<br />

known whether Serenoa repens prevents longterm<br />

complications of BPH such as acute urinary<br />

retention or the need <strong>for</strong> surgical intervention.<br />

The only trial comparing Serenoa repens with<br />

alpha-blockers lasted less than 3 weeks, making<br />

a comparison impossible. Finally, it is possible<br />

that study results were not reported if there were<br />

no improvements in symptoms or flow measures<br />

(publication bias). There are two placebocontrolled<br />

studies involving 298 men that were<br />

scheduled <strong>for</strong> completion in 1998. However,<br />

their results have not yet been reported.<br />

Summary Extracts from the saw palmetto plant,<br />

Serenoa repens, provide modest improvement<br />

in urinary symptoms and flow measures.<br />

Compared with finasteride Serenoa repens<br />

produces similar improvements in symptoms<br />

and flow measures, has fewer adverse<br />

treatment effects and costs less. The long-term<br />

safety and efficacy of Serenoa repens and its<br />

ability to prevent complications from BPH are<br />

not known. Standardized preparations are often<br />

not available. Publication of ongoing trials is<br />

3 | P a g e


encouraged and initiation of long term studies<br />

compared with alpha-blockers would be useful.<br />

Hypoxis rooperi (South African star grass,<br />

bsitosterol) Background Phytosterol extracts<br />

derived from the South African star grass,<br />

Hypoxis rooperi, are popular. The resumed<br />

active constituent is b-sitosterol. Beta-sitosterol<br />

contains a mixture of phytosterols, with smaller<br />

amounts of other sterols, bonded with<br />

glucosides 1. Additionally, the quantity of<br />

bsitosterol- bD-glucoside is often reported. The<br />

product is sold under the trade names Harzol or<br />

Azuprostat. Although the mechanism of action of<br />

b-sitosterols is not known it may be related to<br />

cholesterol metabolism or anti-inflammatory<br />

effects (via interference with prostaglandin<br />

metabolism) 1.<br />

Results of studies <strong>for</strong> randomized controlled<br />

trials evaluated b-sitosterol in 519 men with<br />

symptomatic BPH34±37 (Table 3). All were 464<br />

TJ Wilt et al. double-blinded and lasted between<br />

4 and 26 weeks. Three trials used nonglucosidic<br />

b-sitosterols in doses ranging from 30<br />

mg to greater than 120 mg per day 34,35,37.<br />

The other trial utilized a preparation that<br />

contained 100% bsitosteryl- b-D-glucoside (0.15<br />

mg twice a day) 36. The average age of<br />

participants was 65 years. Men had moderately<br />

severe BPH (mean baseline IPSS score . 15:2;<br />

peak urine flow . 10:2ml s21; prostate size . 49<br />

cc.: Beta-sitosterol provided statistically<br />

significant improvements in urinary symptom<br />

scores and flow measures (Figs 4 and 5). In the<br />

two studies reporting the IPSS score, the WMD<br />

compared with placebo was 24.9 points (95% CI<br />

. 26:3 to 23.5, n . 2 studies) (35% improvement).<br />

The WMD <strong>for</strong> peak urine flow was 3.91 ml s21<br />

(45% improvement) and <strong>for</strong> residual volume the<br />

WMD . 228:62 ml (95% CI . 0:91±6:90; n . 4<br />

studies) (29% improvement). Betasitosterol did<br />

not reduce prostate size and the trial using<br />

100% b-sitosteryl- b-D-glucoside (WA184) did<br />

not show improvement in urinary flow rates.<br />

Adverse events were infrequent and mild.<br />

Withdrawal rates were less than 10% and did<br />

not differ from placebo.<br />

An extract from South African star grass, b-<br />

sitosterol, improved urologic symptoms and flow<br />

measures. However, the existing evidence is<br />

limited to trials of short duration, relatively few<br />

patients studied and lack of standardized b-<br />

sitosterol preparations. Their long term<br />

effectiveness, safety and ability to prevent BPH<br />

complications are not known. Secale cereale<br />

<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />

(rye-grass pollen) Background Rye pollen<br />

extract is prepared from the rye-grass, Secale<br />

cereale. It is used by millions of men worldwide<br />

and is a registered pharmaceutical throughout<br />

Western Europe, Japan, Korea and Argentina<br />

38. In the United States, Cernilton is used as a<br />

nutritional supplement by approximately 5000<br />

men 39. One dose contains 60 mg of Cernitin<br />

T60, a water-soluble pollen extract fraction, and<br />

3 mg of Cernitin GBX, an acetone soluble pollen<br />

extract fraction 38. The acetone-soluble fraction<br />

was found to contain b-sterols 40. In vitro<br />

studies suggest that Cernilton may have antiandrogenic<br />

effects, relax urethral smooth muscle<br />

tone and increase bladder muscle contraction,<br />

or may act on the alpha-adrenergic receptors<br />

and relax the internal and external sphincter<br />

muscles 41±43.<br />

<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />

467 Results of studies A total of 444 men have<br />

been enrolled in two placebo-controlled .n . 163.<br />

and two comparative trials lasting from 12 to 24<br />

weeks 44±47 (Table 4). Three studies were<br />

double-blinded 44,45,47. The mean age of<br />

participants was 69 years. Differences in the<br />

control agents and methods of reporting results<br />

did not permit all studies to be combined in a<br />

meta-analysis. However, three studies reported<br />

symptom scores or measured symptom<br />

Improvement 45±47. Nocturia was reported in<br />

three studies 44,45,47 and all studies reported<br />

peak urine flow and residual urine volume. Data<br />

from all studies were consistent with<br />

improvement in symptoms and urinary flow.<br />

Cernilton improved ‘self-rated urinary symptoms’<br />

versus placebo and Tadenan, an extract from<br />

Pygeum africanum 46. Almost 70% men taking<br />

Cernilton reported symptom improvement<br />

compared with 29% taking placebo. Obstructive<br />

and irritative symptom scores improved from<br />

baseline by 60% in men taking Cernilton<br />

compared with 40% with Tadenan. Cernilton<br />

reduced nocturia compared with placebo and<br />

Paraprost, a pharmacologic treatment used<br />

primarily in Japan containing 265 mg of L-<br />

glutamic acid, 100 mg of Lalanine and 45 mg of<br />

aminoacetic acid 47. Versus placebo, there was<br />

a two-fold improvement in the percentage of<br />

men reporting improvement in nocturia (63% vs.<br />

31%) 44,45.<br />

Compared with Paraprost, Cernilton reduced<br />

nocturia by 0.40 times per evening. The only<br />

adverse event reported was mild nausea.<br />

Although the results suggest that Cernilton<br />

4 | P a g e


provided modest benefit there are limitations to<br />

the evidence. The longest treatment duration<br />

was 24 weeks. Only one study reported results<br />

from a standardized and validated urologic<br />

symptom scale. While the manufacturer<br />

suggests two to four tablets or capsules daily,<br />

the dosages and standardization of preparation<br />

were not usually reported. The most frequently<br />

reported amount was two Cernilton capsules<br />

three times per day.<br />

Summary<br />

The evidence suggests that an extract from ryegrass<br />

pollen, Cernilton, is well tolerated and<br />

modestly improves urologic symptoms.<br />

However, trials were of short duration, enrolled<br />

relatively few patients, and lacked standard<br />

product preparation. Additionally, there was<br />

infrequent use of validated symptom scale<br />

scores. It does not improve urinary flow<br />

measures and the long-term safety and<br />

effectiveness is not known.<br />

Pygeum africanum (African plum)<br />

Background<br />

Traditionally, the bark of the African plum tree<br />

(Pygeum africanum) was collected and<br />

powdered, then drunk as a tea to improve<br />

genito-urinary symptoms. Purified bark extracts<br />

have been used throughout Europe <strong>for</strong> the past<br />

30 years. The postulated active components<br />

include phytosterols, especially b-sitosterols,<br />

pentacyclic triterpenoids and esters of longchain<br />

fatty alcohols. Pygeum africanum extract<br />

may suppress LUTS by reducing bladder<br />

hyperreactivity, decreasing inflammation, and<br />

protecting against abnormal prostate growth 48.<br />

A 1995 review identified 12 double-blind,<br />

placebo controlled studies involving 717 men<br />

with BPH 46, 49±63 (Table 5). Most studies<br />

used a Pygeum extract under the trade name<br />

Tadenan with doses ranging from 75 to 200 mg<br />

day 21. All studies were at least 16 weeks in<br />

duration. More than half the studies measured<br />

peak urinary flow and all but one measured<br />

urinary frequency. Standardized and validated<br />

symptom scores were not utilized and there was<br />

no pooled estimate of treatment effect size or<br />

adverse events. The majority of studies noted an<br />

improvement in nocturia compared with placebo.<br />

An ongoing double-blind placebo-controlled<br />

study is evaluating Tadenan (100 mg and 400<br />

<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />

mg) in 750 men with symptomatic BPH. The<br />

primary endpoint is a mean reduction in the<br />

IPSS score between baseline and 6 months.<br />

However, the results have not been reported. In<br />

five small-scale studies involving 183 men, P.<br />

africanum was compared with active drug or<br />

therapy 50,57,63. Two studies involved plant<br />

extracts (sitosterin and extract of Radix urticae<br />

urtae) 50. The results Fig. 5 Effect of b-sitosterol<br />

on peak urine flow vs. placebo 468 TJ Wilt et al.<br />

indicate that Pygeum reduced nocturia more<br />

than comparators in the 3 studies reporting this<br />

endpoint. However, in two of these studies there<br />

were no statistical comparisons. Since the<br />

publication of this review there have been two<br />

additional trials utilizing Pygeum. One was a<br />

study utilizing a combination of Pygeum with<br />

Urtica and is discussed in the section on Urtica<br />

59. The other trial demonstrated that Pygeum<br />

was less effective than Cernilton in improving<br />

‘self-rated urinary symptoms’ 46. Obstructive<br />

and irritative symptom scores improved from<br />

baseline by 60% in men taking Cernilton<br />

compared with 40% in men taking Tadenan.<br />

Summary<br />

Extracts from the African plum tree, Pygeum<br />

africanum may be a useful treatment option <strong>for</strong><br />

BPH. However, inadequacies in the reporting of<br />

outcomes limit the ability to estimate its safety<br />

and efficacy. An ongoing trial should provide<br />

much needed in<strong>for</strong>mation on the short-term<br />

effectiveness and tolerability of Pygeum<br />

africanum.<br />

Urtica dioica (stinging nettle)<br />

Background<br />

Extracts from roots of the stinging nettle are<br />

often used in Germany <strong>for</strong> the treatment of BPH.<br />

The extracts contain a mixture of water- and<br />

alcohol-soluble compounds with extraction<br />

procedures varying from company to company.<br />

Proposed mechanisms of action include<br />

inhibition of <strong>prostatic</strong> growth factor including<br />

blocking the conversion of testosterone to<br />

dihydrostersterone 1. Results of studies There<br />

have been five randomized trials evaluating<br />

stinging nettle. Three of these involved<br />

combinations with other phytotherapeutic agents<br />

(Pygeum and Sabal), making it difficult to<br />

evaluate the efficacy of stinging nettle alone<br />

26,30,59. Furthermore, one of these studies<br />

merely compared two different doses of a<br />

5 | P a g e


combined extract of Urtica and Pygeum59. The<br />

report by Sokeland compared a combination of<br />

Sabal and Urtica (PRO 160/120) extract with<br />

finasteride and placebo30. This trial lasted 12<br />

weeks and evaluated 543 men. Compared with<br />

finasteride there were no differences in IPSS<br />

scores (24.8 vs. 25.8 IPSS points), peak urine<br />

flow or residual urine volume. More adverse<br />

events were associated with finasteride,<br />

including more cases of erectile dysfunction,<br />

diminished ejaculation volume, and headaches.<br />

Compared with placebo, the combination of<br />

Sabal±Urtica (Prostagutt) improved IPSS scores<br />

by 17% (23.5 IPSS points) 26. One placebocontrolled<br />

study lasting 3 months compared a<br />

liquid preparation of stinging nettle with placebo<br />

in 41 men with BPH64. An improvement in IPSS<br />

scores was noted in men taking stinging nettle.<br />

However, because of unacceptable taste this<br />

preparation has been removed from the market.<br />

Another placebo-controlled trial examined the<br />

effectiveness of Urticae extract capsules65.<br />

Although improvements in peak urine flow and<br />

total voided volume were reported, there was no<br />

difference in urologic symptoms. Additionally,<br />

24% of men (6/25) taking Urticae withdrew from<br />

the study; half of them due to unspecified side<br />

effects.<br />

Summary<br />

Evidence from randomized trials suggests<br />

combination preparations of Urticae appear to<br />

provide some benefit <strong>for</strong> treatment of lower<br />

urinary tract symptoms, although stinging nettle<br />

extracts alone do not appear to be beneficial.<br />

Additional randomized controlled trials need to<br />

be conducted be<strong>for</strong>e Urticae can be<br />

recommended as an effective option <strong>for</strong> the<br />

treatment of LUTS.<br />

Curcubita pepo (pumpkin seed)<br />

Results of studies<br />

There has been only one small-scale<br />

randomized trial of short duration that has<br />

evaluated the efficacy of pumpkin seed<br />

extracts16. This study evaluated 55 men, lasted<br />

<strong>for</strong> 12 weeks and utilized a preparation that<br />

included pumpkin seed, Curcubita pepo, and<br />

Sabal serrulata (Curbicin 160 mg three times a<br />

day). Compared with placebo, Curbicin<br />

improved self-rating of urinary symptoms (85%<br />

noted improvement vs. 11% taking placebo) and<br />

nocturia. Residual urine volume was reduced by<br />

<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />

31% (42.5 cc) compared with only 6.5% (7.6 cc)<br />

with placebo. Because the study utilized a<br />

combination preparation the reported<br />

improvement in urologic symptoms and flow<br />

measures cannot be clearly attributed to<br />

pumpkin seeds.<br />

Summary<br />

There is no convincing evidence that extracts of<br />

pumpkin seed alone improve urologic symptoms<br />

or flow measures. They may provide<br />

improvement in urinary symptoms and flow<br />

measures when used in combination with Sabal<br />

serrulata. Randomized controlled trials need to<br />

be conducted. Recommendations and<br />

conclusions Should physicians recommend plant<br />

extracts <strong>for</strong> treatment of BPH Despite their<br />

popularity and the existence of over 40<br />

randomized controlled trials involving nearly<br />

5000 men, the available data do not yet provide<br />

clear evidence of efficacy <strong>for</strong> most<br />

phytotherapeutic products. Extracts of saw<br />

palmetto (Serenoa repens) (alone or in<br />

combination with other phytotherapeutic<br />

products) have the strongest evidence <strong>for</strong><br />

efficacy and tolerability. They appear to be a<br />

useful option <strong>for</strong> improving lower urinary tract<br />

symptoms and flow measures. Rye-grass pollen<br />

(Secale cereale) and South African star grass<br />

(Hypoxis rooperi, b-sitosterol) also appear to<br />

improve symptoms and are well tolerated.<br />

However, the evidence is <strong>Phytotherapy</strong> <strong>for</strong><br />

<strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong> 469 less strong <strong>for</strong><br />

these products. African plum tree bark (Pygeum<br />

africanum) has been studied extensively but<br />

inadequate reporting of outcomes limits the<br />

ability to conclusively recommend it. There is no<br />

convincing evidence supporting the use of<br />

pumpkin seed (Curcubita pepo) or stinging nettle<br />

(Urtica dioica) extracts alone <strong>for</strong> treatment of<br />

BPH. They may be effective in combination with<br />

other phytotherapeutic products. The<br />

widespread use of phytotherapy attests to the<br />

popularity of plant extracts <strong>for</strong> treatment of BPH<br />

symptoms. They cost less and are better<br />

tolerated, at least in the shortterm, than either<br />

alpha-blockers or finasteride. However, if the<br />

primary goal is to reduce symptoms, alphablockers<br />

such as doxazosin, tamsulosin,<br />

alfuzosin or terazosin seem to be a better choice<br />

than finasteride and probably phytotherapy.<br />

Additionally, plant extracts have not yet been<br />

demonstrated to reduce complications from BPH<br />

or the need <strong>for</strong> surgical intervention in<br />

comparison with interventions such as<br />

6 | P a g e


finasteride33. The Committee on Other Medical<br />

Therapies of the Fourth International<br />

Consultation on BPH concluded that: most plant<br />

extract preparations have different components;<br />

it is not known what mechanisms of action<br />

demonstrated in vitro might be responsible <strong>for</strong><br />

clinical effects; short-term randomized studies<br />

suggest clinical efficacy <strong>for</strong> some preparations;<br />

and studies were usually inadequate due to the<br />

methodology utilized, small numbers and short<br />

duration of study. Of greatest importance is the<br />

completion of additional high quality studies of<br />

long duration to fully evaluate the efficacy and<br />

safety of phytotherapeutic products <strong>for</strong> treatment<br />

of BPH6. Until completion of these studies<br />

and/or regulation of these products the lack of<br />

universal definitions, practices, and standards<br />

within the supplement industry place the onus<br />

on the physician to judge product quality and<br />

efficacy. Manufacturers/companies of plant<br />

extracts often use different extraction processes.<br />

There is no evidence that the extract from one<br />

manufacturer is equivalent to that of another.<br />

Additionally, since the active ingredient(s) are<br />

not known, it is possible that one product might<br />

have clinical efficacy while another does not.<br />

Each company's product must be tested to<br />

evaluate clinical efficacy and bioactivity. The<br />

following recommendations have been made <strong>for</strong><br />

assessing quality measures (these do not<br />

directly address clinical efficacy or safety) in<br />

selecting high-quality and reliable preparations<br />

of phytotherapeutic products manufactured in<br />

the United States66. 1. The manufacturer tests<br />

raw ingredients <strong>for</strong> purity and potency prior to<br />

inclusion in a product. 2. The product is<br />

manufactured in a pharmaceutically licensed<br />

facility registered with the Food and Drug<br />

Administration. 3. The product's ingredients<br />

meet the applicable United States<br />

Pharmacopoeia (USP) standards. 4. All finished<br />

products are analyzed <strong>for</strong> purity and potency<br />

following production by an independent<br />

laboratory using established methods to ensure<br />

that the product meets label claims and is of<br />

good quality. In some cases, this in<strong>for</strong>mation<br />

can be found on product labeling. All reputable<br />

manufacturers will keep certificates of laboratory<br />

results <strong>for</strong> each finished batch of product on file.<br />

These should be available to physicians and<br />

pharmacists on request.<br />

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